Dejerine-Sottas neuropathy (DSN) and Charcot-Marie-Tooth disease type 1 (CMT1) represent genetically heterogeneous inherited peripheral myelinopathies. These conditions constitute part of a spectrum of neuropathy phenotypes ranging in severity from congenital hypomyelinating neuropathy (CHN) to adult onset hereditary neuropathy with liability to pressure palsies (HNPP) (Lupski and Garcia, 2001). At least fifteen genetic loci and six genes have been associated with these disorders; identified genetic causes include altered dosage of peripheral myelin protein 22 (PMP22) or mutations in one of the following genes: PMP22, the gap junction protein β1 gene (GJB1), the myelin protein zero gene (MPZ), the early growth response gene 2 (EGR2), the myotubularin related protein 2 gene (MTMR2), or the N-myc downstream regulated gene 1 (NDRG1)) (Lupski and Garcia, 2001). These genes encode proteins of diverse functions: compact myelin structural proteins (MPZ, PMP22), a non-compact myelin gap junction protein (GJB1), signal transduction proteins (NDRG1, MTMR2), and a transcription factor for late myelin genes (EGR2). Both dominant (PMP22, GJB1, MPZ, EGR2) and recessive (MTMR2, NDRG1, PMP22, EGR2) mutant alleles have been described. Historically considered an autosomal recessive disorder (Dejerine and Sottas, 1893), DSN has been associated predominately with de novo dominant mutations in PMP22 (Roa et al., 1993), MPZ (Hayasaka et al., 1993), or EGR2 (Timmerman et al., 1999), although rare recessive mutations in PMP22 have also been reported (Lupski, 2000; Parman et al., 1999).
In murine embryonic Schwann cells, L-periaxin is initially concentrated in the nuclei but redistributes to the plasma membrane, predominantly adaxonal, with initiation of myelination and then to the abaxonal, Schmidt-Lanterman incisures, and paranodal membranes with maturation of the myelin sheath (Scherer et al., 1995; Sherman and Brophy, 2000). In addition, L-periaxin expression recapitulates this pattern following crush injury (Scherer et al., 1995). This shift in periaxin localization after the spiralization phase of myelination suggests that periaxin participates in membrane-protein interactions that are required to stabilize the mature myelin sheath. As a cytoskeleton-associated protein, L-periaxin may mediate such stabilization by facilitating integration of extracellular signaling through the cytoskeleton which is essential for changes in Schwann cell shape and regulation of gene expression during axonal ensheathment (Fernandez-Valle et al., 1997; Tapon and Hall, 1997). Such a signaling function is supported by the observation that L-periaxin contains a PDZ motif, a domain implicated in the assembly of signaling complexes at sites of cell-cell contact, and a nuclear localization signal (Dytrych et al., 1998; Sherman and Brophy, 2000). Confirming the necessity of periaxin for maintenance of the myelin sheath, Gillespie et al. recently demonstrated that Prx−/− mice ensheathe and myelinate peripheral axons apparently normally but subsequently develop a severe demyelinating neuropathy associated with allodynia (pain from non-noxious stimuli) and hyperalgesia (hypersensitivity to pain) (Gillespie et al., 2000).
However, it was heretofore unknown in the art whether a relationship between the human PRX gene defects and neuropathies such as recessive DSN existed.